Project Summary The goal of this proposal is to develop new synthetic methods for the rapid and precise construction of chiral small molecule building blocks. The focal point of the chemistry described is the use of the phenonium ion as a control element to surmount current synthetic limitations associated with stereo- and regiocontrol. Consequently, this reactive intermediate enables the synthesis of benzylic and homobenzylic stereocenters, which are important motifs found in many pharmaceutical agents. Various phases of this proposal concern expanding upon preliminary results from our laboratory for the development of new methods to generate phenonium ions from unconventional starting materials. In each case, new methods for addressing fundamental synthetic limitations will be obtained as well as a deeper fundamental understanding of phenonium ion formation and reactivity. Execution of the chemistry described will enable modular access to small molecule building blocks of relevance to drug discovery programs, e.g., chiral heterocycles. Relevance to public health: The vast majority of pharmaceutical candidates that make it to market are structurally complex, as defined by the presence of sp3 carbons and stereocenters. Many drug molecules contain common architectures such as benzylic and/or homobenzylic stereocenters. New methods that enable streamlined and modular access to these motifs are, therefore, very important. Supporting this program would result in new synthetic approaches to chiral small molecules containing benzylic and/or homobenzylic stereocenters from simple, readily-available starting materials. In so doing, unsolved challenges related to stereo- and regiocontrol will also be addressed.